AHFS Class:

• Central Nervous System Agents, Miscellaneous 28:92

Generic Name(s):

• Flibanserin

Chemical Name:

• 1,3-Dihydro-1-[2-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]ethyl]-2 H -benzimidazol-2-one

Molecular Formula:

• C₂₀H₂₁F₃N₄O

Flibanserin is a serotonin type 1A (5-hydroxytryptamine [5-HT_1A]) receptor agonist and serotonin type 2A (5-HT_2A) receptor antagonist.1,6,7,8

Hypoactive Sexual Desire Disorder

Flibanserin is used in premenopausal women for the treatment of acquired, generalized hypoactive sexual desire disorder (HSDD), which is characterized by low sexual desire that causes marked distress or interpersonal difficulty and is not due to a coexisting medical or psychiatric condition, problems within the relationship, or the effects of medication or other drug substances.1,2,3,4,12

According to the text revision of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR), HSDD is characterized by persistent or recurrent deficiency or absence of sexual fantasies and desire for sexual activity that causes marked distress or interpersonal difficulty that is not better accounted for by another psychiatric disorder and is not due exclusively to physiologic effects of a drug or other substance or a general medical condition.12 The condition may be categorized as acquired if the sexual dysfunction develops only after a period of normal functioning (i.e., the patient previously had no problems with sexual desire) and generalized if it is not limited to certain types of stimulation, situations, or partners.1,12 Although HSDD is no longer a separate diagnosis in DSM-5, which was published in 2013, some features of the disorder have been incorporated into the diagnosis of female sexual interest/arousal disorder (FSIAD).12,13,27 Other organizations, including the International Society for the Study of Women's Sexual Health (ISSWSH), continue to define HSDD as an independent diagnostic disorder, which is generally characterized by decreased sexual desire and associated clinically important distress.26,27,28

Estimates of the prevalence of HSDD in women vary considerably.18,21,22 The Women's International Study of Health and Sexuality (WISHeS) found that 14% of premenopausal women 20-49 years of age in the US have HSDD.18,21,22 For many women in this study, HSDD was associated with emotional and psychological distress and substantially lower sexual and partner satisfaction.22 Treatment of HSDD may include psychosocial (e.g., psychotherapy, including cognitive behavioral therapy, sex therapy, or couples therapy) and pharmacologic approaches (including bremelanotide and flibanserin).18,26,27,28,29,30 Flibanserin was the first drug labeled by the FDA for the treatment of HSDD in premenopausal women and bremelanotide was the second drug to be labeled for this indication in the US.1,18,21,30 (See Bremelanotide Acetate 28:92.)

The manufacturer states that flibanserin is not indicated for the treatment of HSDD in postmenopausal women† or in men†.1

The manufacturer also states that flibanserin is not indicated to enhance sexual performance†.1

Efficacy of flibanserin for the treatment of HSDD was evaluated in 3 randomized, double-blind, placebo-controlled studies of 24 weeks' duration.1,2,3,4 The 3 studies included 2375 premenopausal women who met DSM-IV-TR criteria for acquired, generalized HSDD of at least 6 months' duration.1,2,3,4 In all 3 studies, flibanserin substantially increased the number of satisfying sexual events per month at week 24 compared with placebo; in addition, a substantial increase in sexual desire was demonstrated in one of the 3 studies.1,2,3,4

Women enrolled in these studies were required to be in a monogamous, heterosexual relationship of at least 1 year's duration with a sexually functional partner, and did not have clinically relevant conditions that would interfere with participation in the study (e.g., psychiatric disorders, ongoing serious medical disorders, substance abuse).2,3,4 After a 4-week baseline period, patients received flibanserin 100 mg or placebo orally once daily at bedtime for 24 weeks.1,2,3,4 The mean age of enrolled patients was 36 years (range: 19-55); approximately 89% of the patients were Caucasian, approximately 10% were black, and 1.5% were Asian.1 The mean duration of the monogamous, heterosexual relationship was 11 years, and the mean duration of HSDD was approximately 5 years.1

The 2 co-primary efficacy end points in these 3 studies were the change at week 24 from baseline in the number of monthly satisfying sexual events (SSEs) and the frequency and intensity of experiencing sexual desire over the previous 4 weeks.1,2,3,4 The SSEs end point in all 3 studies was based on a daily account of the number of sexual events (i.e., sexual intercourse, oral sex, masturbation, or genital stimulation by partner) reported as satisfying by the patient.1,2,3,4 The sexual desire end point in studies 1 and 2 was assessed using a daily electronic diary that recorded patient responses to the statement: “Indicate your most intense level of sexual desire in the last 24 hours.”1,2,3 Responses were rated on a scale ranging from 0 (no desire) to 3 (strong desire) and expressed as a monthly score.1,2,3 In study 3, sexual desire was assessed every 4-8 weeks using the desire domain of the Female Sexual Function Index (FSFI), which consists of 2 questions: “Over the past 4 weeks, how often did you feel sexual desire or interest?” and “Over the past 4 weeks, how would you rate your level (degree) of sexual desire or interest?”1,4 Responses to these questions were rated using a 5-point scale and a monthly score was calculated based on answers to both questions.1,4

In all 3 of the main efficacy studies, flibanserin substantially increased the number of SSEs per month from baseline to week 24 compared with placebo.1,2,3,4 From a mean baseline of 2.5-3 SSEs per 28 days, flibanserin treatment resulted in a median increase over placebo of 0.5-1 SSE per 28 days.1 With regard to sexual desire, there was no substantial difference between flibanserin and placebo when sexual desire was assessed using the daily electronic diary in studies 1 and 2; however, flibanserin demonstrated a substantial improvement over placebo in sexual desire when assessed using the FSFI desire domain in study 3.1,2,3,4 In addition, flibanserin treatment resulted in substantial improvement over placebo on a measure of distress related to HSDD, which was a secondary end point, in the 3 studies.1,2,3,4

A 52-week, open-label extension study evaluated the safety and tolerability of long-term, flexible-dosage flibanserin therapy (50 or 100 mg once daily at bedtime or 25 or 50 mg twice daily) in premenopausal women with HSDD who had completed any of 5 previous flibanserin clinical trials.15 Of the 1723 women with HSDD treated with flibanserin, 962 (about 56%) of them completed 12 months of therapy and 883 of the women were exposed to flibanserin 100 mg daily at bedtime for at least 180 days.15 Flibanserin therapy was generally well tolerated for up to 1 year; the drug was discontinued in approximately 11% of the patients because of adverse effects.15 Most adverse effects were mild to moderate in severity.15 Secondary efficacy end points of this study suggested that improvements in sexual desire and reductions in sexual distress in flibanserin-treated women are maintained or improved during long-term therapy.15

The manufacturer states that flibanserin is not indicated for the treatment of HSDD in postmenopausal women†.1 The drug has been studied in a randomized, double-blind, placebo-controlled clinical study of 24 weeks' duration in 949 naturally postmenopausal women with acquired, generalized HSDD.14 Similar to the inclusion and exclusion criteria used in flibanserin studies in premenopausal women, patients in this study did not have clinically relevant conditions that would interfere with participation in the study; were required to be in a monogamous, heterosexual relationship of at least 1 year's duration with a sexually functional partner; and were not taking other drugs that could interfere with or interact with flibanserin or diminish sexual function.14 Flibanserin therapy in these postmenopausal women with HSDD was found to substantially increase SSEs and sexual desire and reduce the distress associated with low sexual desire compared with placebo; the incidence of adverse effects was similar to that reported in clinical studies in premenopausal women.14 (See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

There are no clinical studies to date that directly compare bremelanotide and flibanserin in patients with HSDD.30

Administration

Flibanserin is administered orally once daily at bedtime ; the drug may be administered without regard to meals.1 Because taking flibanserin during waking hours increases the risk of hypotension, syncope, accidental injury, and CNS depression (e.g., somnolence and sedation), the drug should not be administered at any other time of the day.1 (See CNS Depressant Effects under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

If a dose of flibanserin is missed at bedtime, the missed dose should be skipped and the next dose should be taken at bedtime on the following day; a double dose should not be taken to make up for the missed dose.1 (See Advice to Patients.)

The dose of flibanserin should be skipped if the patient consumed 3 or more standard alcoholic drinks during the evening.1 If 1-2 standard alcoholic drinks were consumed, the patient should allow at least 2 hours to elapse before taking the flibanserin dose at bedtime.1 After flibanserin is taken at bedtime, alcohol should not be consumed until the following day (i.e., at least until the next morning).1 (See Hypotension and Syncope Caused by an Interaction with Alcohol under Warnings/Precautions: Warnings, in Cautions and see also Drug Interactions: Alcohol.)

At least 2 weeks must elapse between discontinuance of a moderate or potent cytochrome P-450 (CYP) 3A4 inhibitor and initiation of flibanserin and at least 2 days should elapse between discontinuance of flibanserin, and initiation of a moderate or potent CYP3A4 inhibitor.1 (See Cautions: Contraindications, see Hypotension and Syncope with CYP3A4 Inhibitors under Warnings/Precautions: Warnings, in Cautions, and see also Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.)

Dosage

Hypoactive Sexual Desire Disorder

The recommended dosage of flibanserin in premenopausal women for the treatment of acquired, generalized hypoactive sexual desire disorder (HSDD) is 100 mg orally once daily at bedtime.1

Flibanserin should be discontinued in women who do not report an improvement in HSDD symptoms after 8 weeks of therapy.1

Special Populations

The manufacturer makes no specific dosage recommendations for patients with renal impairment at this time.1 However, dosage adjustments are unlikely to be necessary because of only minimal increases in flibanserin exposure in patients with mild to severe renal impairment.1

Flibanserin is contraindicated in patients with hepatic impairment.1 (See Hypotension and Syncope in Patients with Hepatic Impairment under Warnings/Precautions: Warnings, in Cautions.)

Contraindications

Concomitant use of moderate or potent cytochrome P-450 (CYP) 3A4 inhibitors.1 (See Hypotension and Syncope with CYP3A4 Inhibitors under Warnings/Precautions: Warnings, in Cautions and also see Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.)

Hepatic impairment.1 (See Hypotension and Syncope in Patients with Hepatic Impairment under Warnings/Precautions: Warnings, in Cautions.)

Warnings/Precautions

Warnings

Hypotension and Syncope Caused by an Interaction with Alcohol

Use of alcohol concomitantly or close together in time (i.e., within 2 hours) with flibanserin increases the risk of severe hypotension and syncope.1 To reduce this risk, patients should allow at least 2 hours to elapse after consumption of 1-2 standard alcoholic drinks before taking flibanserin at bedtime.1 If 3 or more standard alcoholic drinks were consumed during the evening, the flibanserin dose should be skipped.1

One standard alcoholic drink contains 14 g of pure alcohol and is equivalent to a 12-ounce can of beer (5% alcohol content), a 5-ounce glass of wine (12% alcohol content), or 1.5 ounces/shot of distilled spirit (40% alcohol content [80-proof]).1

After flibanserin is taken at bedtime, alcohol should not be consumed until the following day.1 (See Drug Interactions: Alcohol and see also Advice to Patients.)

Hypotension and Syncope with CYP3A4 Inhibitors

Moderate or potent CYP3A4 inhibitors substantially increase flibanserin exposure, which can lead to hypotension and syncope; concomitant use of flibanserin and moderate or potent CYP3A4 inhibitors is therefore contraindicated.1 If a flibanserin-treated patient requires therapy with a moderate or potent CYP3A4 inhibitor, at least 2 days should elapse between discontinuance of flibanserin and initiation of the moderate or potent CYP3A4 inhibitor.1 In cases where the benefit of initiating therapy with a moderate or potent CYP3A4 inhibitor within 2 days of flibanserin discontinuance clearly outweighs the risk of flibanserin-related hypotension and syncope, the patient should be monitored for signs of hypotension and syncope.1 In addition, at least 2 weeks should elapse between discontinuance of the moderate or potent CYP3A4 inhibitor and reinitiation of flibanserin therapy.1 (See Dosage and Administration: Administration and also see Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.)

Concomitant use of flibanserin with multiple weak CYP3A4 inhibitors, which may include dietary or herbal supplements (e.g., ginkgo, resveratrol) or over-the-counter drugs (e.g., cimetidine), also may result in clinically important increases in flibanserin concentrations that may subsequently increase the risk of hypotension and syncope.1 (See Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.)

Hypotension and Syncope in Patients with Hepatic Impairment

Use of flibanserin in patients with any degree of hepatic impairment substantially increases flibanserin concentrations, which can lead to hypotension and syncope.1 Flibanserin is therefore contraindicated in patients with hepatic impairment.1 (See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Other Warnings and Precautions

CNS Depressant Effects

Flibanserin can cause CNS depression (e.g., somnolence, sedation) when given alone;1 the CNS depressant effects appear to be most prominent approximately 1-4 hours after oral administration.9 In 5 placebo-controlled, double-blind trials in premenopausal women with HSDD, somnolence, sedation, or fatigue occurred in 21% of patients receiving flibanserin 100 mg once daily at bedtime compared with 8% of placebo recipients.1 In these clinical trials, a similar incidence of accidental injury was reported in patients receiving flibanserin or placebo (2.7 or 2.5%, respectively); however, 21% of flibanserin recipients compared with 6% of placebo recipients reported adverse reactions consistent with CNS depression within the preceding 24 hours of the accidental injury.1 The risk of CNS depression is increased if flibanserin is taken during waking hours or if the drug is taken with alcohol or other CNS depressants or with drugs that increase flibanserin concentrations (such as CYP3A4 inhibitors).1 (See Dosage and Administration: Administration and see also Drug Interactions.)

The effect of flibanserin on driving performance was evaluated in a randomized, placebo-controlled, crossover study in healthy premenopausal women.1 Single and multiple 100-mg doses of flibanserin at bedtime and single 200-mg doses of flibanserin at bedtime did not impair measures of driving performance or psychomotor performance considered important for driving when assessed 9 hours following bedtime dosing.1 The manufacturer recommends that patients avoid driving, operating complex machinery, or engaging in other activities requiring full alertness until at least 6 hours after a dose of flibanserin.1 (See Advice to Patients.)

Hypotension and Syncope with Flibanserin Alone

Use of flibanserin alone can cause hypotension and syncope.1 In 5 placebo-controlled studies in premenopausal women with HSDD, hypotension was reported in 0.2 and less than 0.1% of patients receiving flibanserin and placebo, respectively, and syncope was reported in 0.4 and 0.2% of patients receiving flibanserin and placebo, respectively.1 The risk of hypotension and syncope is increased if flibanserin is taken during waking hours or in higher than recommended dosages.1

The clinical benefits of flibanserin therapy and the risks of hypotension and syncope should be considered in patients with preexisting conditions that predispose to hypotension.1 Patients who experience presyncope should immediately lie supine and promptly seek medical attention if symptoms do not resolve.1 Prompt medical attention also is advised for patients who experience syncope.1

Mammary Tumors in Female Mice

Flibanserin was associated with 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 human dosage in a 2-year carcinogenicity study.1 Such increases were not observed in male mice or male or female rats.1 The clinical relevance of these findings is unknown.1

Specific Populations

Pregnancy

There are no studies of flibanserin in pregnant women to date.1 In animal studies, fetal toxicity occurred only in conjunction with substantial maternal toxicity, including reduced weight gain and sedation.1 Developmental toxicity, including decreased fetal weight and structural abnormalities, and increases in fetal loss occurred when the drug was administered to pregnant animals at exposures greater than 15 times the exposures achieved with the recommended human dosage.1 The manufacturer states that animal studies cannot exclude the potential for fetal harm.1

Lactation

It is not known whether flibanserin is distributed into human milk.1 Flibanserin is distributed into milk in rats.1 Because of the potential for serious adverse reactions, including sedation, in nursing infants, the manufacturer states that breast-feeding during flibanserin therapy is not recommended.1

Pediatric Use

Flibanserin is not indicated for use in pediatric patients.1 In addition, the effect of age on flibanserin exposure has not been systematically evaluated to date.1

Geriatric Use

Safety and efficacy of flibanserin have not been established in geriatric patients, and the drug is not indicated for use in geriatric patients.1 In addition, the effect of age on flibanserin exposure has not been systematically evaluated to date.1

The manufacturer states that flibanserin is not indicated for treatment of HSDD in postmenopausal women†.1

Because geriatric patients are more likely to be taking other drugs concurrently, some clinicians caution that the risk of potential drug interactions and subsequent adverse effects may be increased in such patients.21 In addition, these clinicians state that geriatric patients may be at greater risk for injury from falls that could result from flibanserin-induced hypotension and/or syncope.21

Hepatic Impairment

Flibanserin is contraindicated in patients with hepatic impairment.1 In a single-dose pharmacokinetic study, systemic exposure to flibanserin was increased 4.5-fold and the half-life of the drug was prolonged (to 26 hours) in patients with mild hepatic impairment (Child-Pugh score of 6) compared with individuals with normal hepatic function.1 The manufacturer states that because of the small number of patients with moderate hepatic impairment in this study, it was not possible to make conclusions about the quantitative effect of moderate hepatic impairment on flibanserin exposure.1 (See Hypotension and Syncope in Patients with Hepatic Impairment under Warnings/Precautions: Warnings, in Cautions.)

Renal Impairment

Results of a single-dose pharmacokinetic study showed only slight increases in flibanserin exposure in patients with mild to moderate (glomerular filtration rate [GFR] 30-80 mL/minute) or severe (GFR less than 30 mL/minute, not requiring dialysis) renal impairment of 1.1- and 1.2-fold, respectively, compared with healthy individuals.1

Pharmacogenomics and Poor CYP2C19 Metabolizers

In a pharmacogenomic study, peak plasma concentrations and exposure of flibanserin were 1.5- and 1.3-fold higher, respectively, in women who were poor metabolizers of CYP2C19 than in extensive metabolizers of CYP2C19.1 The elimination half-life of flibanserin increased from 11.1 hours in extensive CYP2C19 metabolizers to 13.5 hours in poor CYP2C19 metabolizers.1 Syncope occurred in 1 of 9 individuals who were poor CYP2C19 metabolizers and in none of the extensive CYP2C19 metabolizers in this study; the individual who experienced syncope had a 3.2-fold higher flibanserin exposure compared with individuals who were extensive CYP2C19 metabolizers.1

The manufacturer recommends increased monitoring for adverse reactions (e.g., hypotension) in patients who are poor CYP2C19 metabolizers.1 Approximately 2-5% of Caucasians and Africans and approximately 2-15% of Asians are poor CYP2C19 metabolizers.1

Race

In a cross-study comparison between healthy Japanese women and Caucasian women with HSDD, an approximately 1.4-fold higher exposure to flibanserin was observed among Japanese women compared with Caucasian women.1 However, weight-adjusted areas under the concentration-time curve during a dosage interval at steady state (AUC_tau,ss) were similar in both groups, suggesting that weight rather than race contributed to the observed difference in flibanserin exposure.1

Common Adverse Effects

Adverse effects reported in at least 2% of patients receiving flibanserin and at an higher incidence than reported with placebo in controlled studies include dizziness,1 somnolence,1 nausea,1 fatigue,1 insomnia,1 and dry mouth;1 most of these adverse effects began within the first 14 days of treatment.1

Flibanserin is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4 and, to a lesser extent, by CYP2C19.1 In addition, CYP isoenzymes 1A2, 2B6, 2C8, 2C9, and 2D6 contribute minimally (less than 10%) to the metabolism of flibanserin.1,10

Flibanserin inhibits P-glycoprotein (P-gp).1,5,10

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 Inhibitors

Concomitant use of flibanserin with moderate or potent CYP3A4 inhibitors (e.g., antifungal agents [fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole], certain antibiotics [ciprofloxacin, clarithromycin, erythromycin, telithromycin], HCV protease inhibitors [boceprevir and telaprevir, which are no longer commercially available in the US], HIV protease inhibitors [atazanavir, fosamprenavir, nelfinavir, ritonavir, saquinavir], conivaptan, diltiazem, verapamil, nefazodone, grapefruit juice, St. John's wort [ Hypericum perforatum ]) results in increased flibanserin exposure and an increased risk of hypotension, syncope, and CNS depression.1,20 Concomitant use of flibanserin with moderate or potent CYP3A4 inhibitors is therefore contraindicated.1,18 If a flibanserin-treated patient requires therapy with a moderate or potent CYP3A4 inhibitor, at least 2 days should elapse between discontinuance of flibanserin and initiation of the CYP3A4 inhibitor.1 In cases where the benefit of initiating therapy with a moderate or potent CYP3A4 inhibitor within 2 days of flibanserin discontinuance clearly outweighs the risk of flibanserin-related hypotension and syncope, the patient should be monitored for signs of hypotension and syncope.1 In addition, at least 2 weeks should elapse between discontinuance of the moderate or potent CYP3A4 inhibitor and reinitiation of flibanserin therapy.1 (See Hypotension and Syncope with CYP3A4 Inhibitors under Warnings/Precautions: Warnings, in Cautions.)

Concomitant use of flibanserin with multiple weak CYP3A4 inhibitors, which may include dietary or herbal supplements or over-the-counter (OTC) drugs (e.g., cimetidine, fluoxetine, ginkgo, oral contraceptives, ranitidine, resveratrol), also can result in increased flibanserin exposure, which may increase the risk of adverse effects (e.g., hypotension, syncope, CNS depression).1 Patients should be informed about the increased risk of adverse effects when flibanserin is used with multiple weak CYP3A4 inhibitors.1 (See Drug Interactions: Hormonal Contraceptives and also see Advice to Patients.)

Fluconazole

In a pharmacokinetic drug interaction study, concomitant use of flibanserin (single 100-mg dose) and fluconazole (a moderate CYP3A4 inhibitor, moderate CYP2C9 inhibitor, and potent CYP2C19 inhibitor; 400-mg loading dose followed by 200 mg once daily for 5 days) resulted in a 7- and 2.2-fold increase in exposure and peak plasma concentrations of flibanserin, respectively.1,10 In this study, 3 of 15 individuals (20%) who received the drugs concomitantly experienced hypotension or syncope requiring intervention; one of these individuals became unresponsive with a blood pressure of 64/41 and required emergency treatment with IV saline.1 The study was discontinued because of these adverse events.1 No cases of hypotension or syncope requiring intervention were reported when flibanserin or fluconazole was administered alone.1

Itraconazole

Concomitant use of flibanserin (single 50-mg dose) and the potent CYP3A4 inhibitor itraconazole (400-mg loading dose followed by 200 mg daily for 4 days) in healthy males and females resulted in a 2.6- and 1.7-fold increase in exposure and peak plasma concentrations of flibanserin, respectively.1,10 The lower dosage of itraconazole used in this study did not maximally inhibit the CYP3A4 isoenzyme.1,5

Ketoconazole

In a pharmacokinetic study, concomitant use of flibanserin (single 50-mg dose) and the potent CYP3A4 inhibitor ketoconazole (400 mg daily for 5 days) increased exposure and peak plasma concentrations of flibanserin by 4.5- and 1.8-fold, respectively.1 Of 24 individuals in the study, syncope occurred in one individual (4%) receiving flibanserin with ketoconazole, one individual (4%) receiving flibanserin alone, and in no one receiving ketoconazole alone.1

CYP2C19 Inhibitors

Based on pharmacogenomic data, concomitant use of flibanserin with potent CYP2C19 inhibitors (e.g., certain antifungals [e.g., fluconazole], benzodiazepines, proton-pump inhibitors, and selective serotonin-reuptake inhibitors [e.g., fluvoxamine]) may result in increased flibanserin exposure and therefore an increased risk of hypotension, syncope, and CNS depression.1,18,20 Patients should be advised of the increased risk of adverse effects when flibanserin is used concurrently with a potent CYP2C19 inhibitor.1 (See Advice to Patients.)

CYP3A4 Inducers

Concomitant use of flibanserin with a CYP3A4 inducer (e.g., carbamazepine, etravirine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, St. John's wort [ Hypericum perforatum ]) may result in substantially decreased systemic exposure to flibanserin.1 Therefore, the manufacturer states that concomitant use of flibanserin and CYP3A4 inducers is not recommended.1

Etravirine

Etravirine, a moderate CYP3A4 inducer, at steady-state concentrations decreased systemic exposure of flibanserin by approximately 21%.1,10

Rifampin

Concomitant use of flibanserin (single 100-mg dose) and the potent CYP3A4 inducer rifampin (600 mg daily for 7 days) decreased systemic exposure of flibanserin by approximately 95%.1,10

Substrates of P-glycoprotein Transport Systems

Flibanserin appears to be an inhibitor of P-glycoprotein (P-gp).1,5,10 Concomitant use of flibanserin with P-gp substrates (e.g., digoxin, sirolimus) may result in increased concentrations of the P-gp substrate and possible toxicity.1 The manufacturer of flibanserin recommends more frequent monitoring of serum concentrations of P-gp substrates that have a narrow therapeutic index (e.g., digoxin) when the drugs are used concomitantly.1

Digoxin

Concomitant administration of flibanserin (100 mg daily for 5 days) and digoxin (a P-gp substrate; single 0.5-mg dose) in healthy men and women increased exposure and peak concentrations of digoxin by 2- and 1.5-fold, respectively, compared with digoxin administration alone.1 Because of the potential for digoxin toxicity, the manufacturer of flibanserin recommends more frequent monitoring of digoxin concentrations when the drugs are used concomitantly.1

Drugs Metabolized by Hepatic Microsomal Enzymes

Bupropion

Concomitant administration of flibanserin (50 mg twice daily for 2 days then 100 mg daily for 13 days) and the CYP2B6 substrate bupropion (150 mg twice daily for 8 days, starting on day 6 of flibanserin therapy) in healthy women did not affect the pharmacokinetics of bupropion.1 AUC and peak plasma concentrations of hydroxybupropion decreased by 9 and 11%, respectively.1

Simvastatin

Following concomitant administration of flibanserin (50 mg twice daily for 4 days) and the CYP3A4 substrate simvastatin (single 40-mg dose) in healthy males and females, exposure and peak concentrations of simvastatin increased by 1.3- and 1.2-fold, respectively, and exposure and peak concentrations of simvastatin acid increased by 1.5- and 1.4-fold, respectively.1,10

Alcohol

Use of flibanserin and alcohol concomitantly or close together in time (i.e., within 2 hours) increases the risk of severe hypotension, syncope, and CNS depression compared with flibanserin or alcohol use alone.1,10 Patients should allow at least 2 hours to elapse after consumption of 1-2 standard alcoholic drinks before taking flibanserin at bedtime.1 If 3 or more standard alcoholic drinks were consumed during the evening, the flibanserin dose should be skipped.1 After flibanserin is taken at bedtime, alcohol should not be consumed until the following day.1 (See Hypotension and Syncope Caused by an Interaction with Alcohol under Warnings/Precautions: Warnings, in Cautions.)

The pharmacokinetics of flibanserin do not appear to be substantially altered by concurrent consumption of alcohol when studied for a limited period of time (up to 4 hours post-dosing),1,10,23 suggesting that the increased risk of hypotension- and syncope-related events may result from a pharmacodynamic interaction between flibanserin and alcohol.23

In five phase 3, randomized, double-blind, placebo-controlled, 24-week clinical trials in premenopausal women with HSDD, alcohol use was not restricted and patients were instructed to continue their usual habits with regard to alcohol use.5,23 However, alcohol use was not recorded during the randomized treatment periods and therefore the frequency and quantity of alcohol use among flibanserin-treated patients in these clinical trials are not known.5,23 In a pooled analysis of these trials, approximately 58% of patients who received flibanserin reported some level of baseline alcohol use; adverse effects (e.g., fatigue, dizziness, sedation) occurred more frequently in these patients than in flibanserin-treated patients who reported no baseline alcohol use.23

The effects of alcohol and flibanserin were evaluated in several interaction studies in which alcohol was administered at the same time or at various times in relation to flibanserin administration.1,24 These studies used 0.2-, 0.4-, 0.6-, or 0.8-g/kg doses of alcohol, which are equivalent to 1, 2, 3, or 4 alcoholic drinks in a 70-kg person, respectively (one alcoholic drink is equivalent to a 12-ounce can of beer with 5% alcohol content, a 5-ounce glass of wine with 12% alcohol content, or 1.5 ounces of 80-proof spirit).1,24

In a randomized, placebo-controlled, crossover study in 96 healthy premenopausal women, administration of flibanserin (single 100-mg dose) in combination with alcohol (single 0.2-, 0.4-, or 0.6-g/kg dose consumed over 10 minutes) in the morning was associated with higher incidences of dizziness, hypotension, and orthostasis compared with administration of either flibanserin or alcohol alone.1,24 Somnolence occurred in 81-89% of individuals who received flibanserin plus alcohol and in 84% of individuals who received flibanserin alone compared with 25-41% of individuals who received alcohol alone.1 Dizziness was reported in 27-40% of individuals who received flibanserin plus alcohol compared with 31% of individuals who received flibanserin alone and 6-20% of individuals who received alcohol alone.1 No cases of syncope or hypotension requiring therapeutic intervention occurred during this study;1 however, the study had limitations that did not allow for adequate assessment of these risks.1,25 The study excluded individuals with a history of syncope, orthostatic hypotension, hypotensive events, or dizziness, and those with resting systolic or diastolic blood pressure less than 110 or 60 mm Hg, respectively.1 In addition, during the study, individuals who had blood pressure less than 90/60 mm Hg or were symptomatic (e.g., dizzy) while in the semi-recumbent position were not allowed to stand for orthostatic measurements until it was considered safe for them to change position.1,25 A greater number of individuals who received flibanserin plus alcohol had missing or delayed orthostatic measurements (e.g., due to hypotension or dizziness), particularly during the time of peak plasma flibanserin concentrations, compared with those who received alcohol or flibanserin alone.1,25 Such a pattern of missing or delayed orthostatic measurements is concerning for a risk of hypotension and syncope if those individuals had been allowed to stand.1,25

In an earlier randomized, double-blind, crossover alcohol interaction study in 25 healthy individuals (23 men and 2 premenopausal women), administration of flibanserin in combination with alcohol was associated with a higher incidence of hypotension, syncope, and somnolence compared with administration of either flibanserin or alcohol alone.1,23 In this study, flibanserin (single 100-mg dose) and alcohol (single 0.4- or 0.8-g/kg dose of alcohol consumed over 10 minutes) were administered alone or in combination in the morning.1,23 Somnolence was reported in 74 or 92% of individuals following administration of flibanserin with 0.4 or 0.8 g/kg of alcohol, respectively, compared with 67% of individuals following administration of flibanserin alone.1,23 Hypotension or syncope requiring therapeutic intervention (e.g., ammonia salts and/or placement in supine or Trendelenburg position) occurred in 4 of 23 individuals (17%) following administration of flibanserin with 0.4 g/kg of alcohol; all 4 of these individuals were men.1,23 Reductions in systolic or diastolic blood pressure in these individuals ranged from 28-54 or 24-46 mm Hg, respectively.1,23 Orthostatic hypotension occurred in 6 of 24 individuals (25%) following administration of flibanserin with 0.8 g/kg of alcohol; reductions in systolic or diastolic blood pressure ranged from 22-48 or 0-27 mm Hg, respectively, and one individual required therapeutic intervention.1 There were no reported adverse events requiring therapeutic intervention when flibanserin or alcohol was administered alone.1,23

The effect of time between administration of alcohol and flibanserin was evaluated in a placebo-controlled study in 64 healthy premenopausal women.1 Following administration of flibanserin or placebo for 3 days to achieve steady state, women consumed a 0.4-g/kg dose of alcohol and flibanserin 100 mg or placebo was administered 2, 4, or 6 hours later.1 The study excluded individuals with current or a history of orthostatic hypotension and those with a history of hypotension, syncope, or dizziness.1 The incidences of orthostatic hypotension and hypotension at all time points were similar in individuals who received alcohol before flibanserin and those who received flibanserin or alcohol alone.1 Three individuals were unable to stand because of dizziness or hypotension; 2 of these individuals received alcohol and flibanserin separated by 2 and 6 hours and one received flibanserin alone.1 Somnolence or dizziness occurred in 35-53 or 5-13% of women, respectively, receiving flibanserin at least 2 hours after alcohol consumption, compared with 5-8 or 0-3% of women, respectively, who received alcohol alone and 50 or 12% of women, respectively, who received flibanserin alone.1

In another alcohol interaction study, the effect of alcohol consumed with an evening meal followed by flibanserin at bedtime was evaluated in 24 premenopausal women.1 In this study, women consumed 0.4 g/kg of alcohol during the evening meal followed by a 100-mg dose of flibanserin at bedtime 2.5-4 hours later.1 The incidence of hypotension upon rising the following morning in women who consumed alcohol with the evening meal followed by flibanserin (23%) was not greater than that in individuals who received flibanserin alone (36%) or alcohol alone (23%).1 No cases of syncope, somnolence, or dizziness were reported in this study.1 Conclusions from this study are limited since blood pressure and orthostatic measurements were not taken until the morning after flibanserin administration.1

CNS Depressants

Flibanserin alone can cause CNS depression and concomitant use with other CNS depressants (e.g., benzodiazepines, diphenhydramine, sedative and hypnotic drugs, opiates) may increase the risk of CNS depression.1 Patients should be advised of the increased risk of adverse effects when flibanserin is used with other CNS depressants.1 (See CNS Depressant Effects under Warnings/Precautions: Other Warnings and Precautions, in Cautions; see Drug Interactions: Alcohol; and see also Advice to Patients.)

Grapefruit

Concomitant administration of flibanserin (single 100-mg dose) and grapefruit juice (240 mL), a moderate CYP3A4 inhibitor, in healthy females increased flibanserin exposure and peak concentrations by 1.4- and 1.1-fold, respectively, compared with flibanserin administration alone.1 Concomitant use of grapefruit juice and flibanserin is contraindicated.1 (See CYP3A4 Inhibitors under Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes and see also Advice to Patients.)

Hormonal Contraceptives

Concomitant use of flibanserin and oral contraceptives, which are weak CYP3A4 inhibitors, may result in minor increases in flibanserin exposure.1,5,10 In a meta-analysis of pharmacokinetic data from phase 1 studies, AUC and peak concentrations of flibanserin were 1.4- and 1.3-fold higher, respectively, in individuals receiving oral contraceptives compared with those who were not taking oral contraceptives.1,10 In addition, patients using hormonal contraceptives (i.e., subcutaneous, injectable, intravaginal, or oral) while receiving flibanserin in 4 clinical trials experienced a higher incidence of adverse effects (including nausea, dizziness, somnolence, and fatigue) compared with those who were not receiving hormonal contraceptives.1,10

In a pharmacokinetic study in healthy women, concomitant use of flibanserin (100 mg once daily for 2 weeks) and a single dose of an oral contraceptive containing ethinyl estradiol and levonorgestrel did not substantially alter the pharmacokinetics of the individual oral contraceptive components.1

Concomitant use of flibanserin with multiple weak CYP3A4 inhibitors, including oral contraceptives, may result in increased flibanserin exposure that may increase the risk of hypotension and syncope.1 Patients should be informed about the increased risk of adverse effects when flibanserin is used with multiple weak CYP3A4 inhibitors.1 (See Advice to Patients.)

Paroxetine

In a pharmacokinetic study, concomitant administration of flibanserin (50 mg twice daily) and the potent CYP2D6 inhibitor paroxetine (20 mg daily for 3 days followed by 40 mg daily for 7 days) decreased flibanserin exposure by approximately 4%.1 Flibanserin pharmacokinetics were not substantially affected by concomitant use of paroxetine.1

Description

Flibanserin is a serotonin type 1A (5-hydroxytryptamine [5-HT_1A]) receptor agonist and 5-HT_2A receptor antagonist.1,6,7,8 The drug also is a moderate antagonist at 5-HT_2B, 5-HT_2C, and dopamine D₄ receptors.1,6,8 The precise mechanism of action of flibanserin in the treatment of hypoactive sexual desire disorder (HSDD) in premenopausal women is not fully understood,1,6,7 but is thought to be related to enhancement of dopaminergic and noradrenergic activity and reduction of serotonergic activity in the prefrontal cortex.6,7 Generally, dopamine and norepinephrine are thought to be excitatory and serotonin inhibitory to sexual desire and arousal.6,7,16,17 It has been suggested that flibanserin-induced activation of inhibitory 5-HT_1A receptors and inhibition of excitatory 5-HT_2A receptors may synergistically inhibit glutamate release from pyramidal neurons in the prefrontal cortex, resulting in decreased serotonin release and increased dopamine and norepinephrine concentrations in certain areas of the prefrontal cortex.6,7,16 Those prefrontal brain areas are consistent with the same sites of abnormal neuroimaging described in patients with reduced sexual interest and desire.7,17

Following oral administration of a single 100-mg dose of flibanserin in healthy premenopausal women, peak plasma concentrations of the drug usually are attained within approximately 45 minutes (range: 0.75-4 hours).1,9 Flibanserin undergoes extensive first-pass metabolism and has an absolute oral bioavailability of 33%.1,9 The drug exhibits dose-proportional pharmacokinetics following administration of single oral doses over the dosage range of 100-250 mg.1,9 Steady-state concentrations are achieved after 3 days of dosing; exposure with once-daily dosing of flibanserin was 1.4-fold higher compared with single-dose administration.1 Peak plasma concentrations and exposure of flibanserin are increased and time to peak plasma concentrations is delayed when the drug is taken with food.1 The drug is approximately 98% bound to plasma proteins, mainly to albumin.1 Flibanserin is extensively metabolized, principally by cytochrome P-450 (CYP) isoenzyme 3A4 and to a lesser extent by CYP2C19, to at least 35 metabolites, which mostly are present in low plasma concentrations; 2 of these metabolites appear in substantial concentrations in plasma and are pharmacologically inactive.1 CYP isoenzymes 1A2, 2B6, 2C8, 2C9, and 2D6 appear to contribute minimally (i.e., less than 10%) to the drug's metabolism.1 Following administration of a single, radiolabeled dose of flibanserin, 44 and 51% of administered radioactivity was recovered in the urine and feces, respectively.1 The mean terminal half-life of flibanserin is approximately 11 hours.1

Advice to Patients

Importance of advising patients to read the manufacturer's medication guide prior to initiating flibanserin therapy and each time the prescription is refilled.1

Importance of advising patients to take the prescribed dose of flibanserin exactly as directed (once daily at bedtime) and not to take the drug at any other time of the day, since taking flibanserin during waking hours increases the risk of hypotension, syncope, accidental injury, and CNS depression.1

If a dose of flibanserin is missed at bedtime, the missed dose should be skipped and the next dose should be taken at bedtime on the following day.1 Importance of advising patients not to take the missed dose the next morning or 2 doses of the drug at the same time.1

Importance of informing patients that taking flibanserin concomitantly or close together in time (i.e., within 2 hours) with alcohol increases the risk of severe hypotension and syncope.1 To reduce this risk, patients should be advised to wait at least 2 hours if they consumed 1-2 standard alcoholic drinks before taking flibanserin at bedtime.1 Patients should also be advised to skip the bedtime dose of flibanserin if they consumed 3 or more standard alcoholic drinks during that evening.1 After taking flibanserin at bedtime, patients should be advised that alcohol should not be consumed until the following day.1 (See Hypotension and Syncope Caused by an Interaction with Alcohol under Warnings/Precautions: Warnings, in Cautions.)

Importance of informing patients that the risk of severe hypotension and syncope is increased when flibanserin is used concurrently with moderate or potent cytochrome P-450 (CYP) isoenzyme 3A4 inhibitors or used in patients with hepatic impairment.1 Importance of informing patients that use of moderate or potent CYP3A4 inhibitors is contraindicated during flibanserin therapy and that the drug also is contraindicated in patients with hepatic impairment.1 Patients should ask about potential drug interactions before beginning any new prescription or over-the-counter medication (e.g., cimetidine) or using other products that contain CYP3A4 inhibitors (e.g., grapefruit juice, ginkgo, resveratrol, St. John's wort).1 (See Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.) Importance of advising patients who experience presyncope or lightheadedness to lie down and to seek medical attention if symptoms persist.1

Risk of somnolence or sedation.1 Importance of advising patients that concomitant use of other CNS depressants (e.g., alcohol, benzodiazepines, sedative and hypnotic drugs, opiates, diphenhydramine) and taking flibanserin during waking hours can increase the risk of CNS depression.1,10 Importance of advising patients not to drive, operate complex machinery, or engage in other activities requiring full alertness until at least 6 hours after taking a dose of flibanserin and until the effects of the drug are known.1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed; importance of advising women to avoid breast-feeding during flibanserin therapy.1

Importance of informing clinician of existing or contemplated concomitant therapy, including prescription, OTC, and recreational drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., psychiatric disorders, liver disease, conditions that may predispose to hypotension).1

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Sprout Pharmaceuticals, Inc. Addyi^® (flibanserin) film-coated tablets prescribing information. Raleigh, NC; 2019 Oct.

2. DeRogatis LR, Komer L, Katz M et al. Treatment of hypoactive sexual desire disorder in premenopausal women: efficacy of flibanserin in the VIOLET Study. J Sex Med . 2012; 9:1074-85. [PubMed 22248038]

3. Thorp J, Simon J, Dattani D et al. Treatment of hypoactive sexual desire disorder in premenopausal women: efficacy of flibanserin in the DAISY study. J Sex Med . 2012; 9:793-804. [PubMed 22239862]

4. Katz M, DeRogatis LR, Ackerman R et al. Efficacy of flibanserin in women with hypoactive sexual desire disorder: results from the BEGONIA trial. J Sex Med . 2013; 10:1807-15. [PubMed 23672269]

5. US Food and Drug Administration. Center for Drug Evaluation and Research: Application number 022526Orig1s000: Summary review. 2015 Feb 18. From FDA website. [Web]

6. Stahl SM, Sommer B, Allers KA. Multifunctional pharmacology of flibanserin: possible mechanism of therapeutic action in hypoactive sexual desire disorder. J Sex Med . 2011; 8:15-27. [PubMed 20840530]

7. Stahl SM. Mechanism of action of flibanserin, a multifunctional serotonin agonist and antagonist (MSAA), in hypoactive sexual desire disorder. CNS Spectr . 2015; 20:1-6. [PubMed 25659981]

8. Borsini F, Evans K, Jason K et al. Pharmacology of flibanserin. CNS Drug Rev . 2002; 8:117-42. [PubMed 12177684]

9. Trocóniz IF, Boland K, Staab A. Population pharmacokinetic/pharmacodynamic model for the sedative effects of flibanserin in healthy volunteers. Pharm Res . 2012; 29:1518-29. [PubMed 22219166]

10. Sprout Pharmaceuticals, Inc. Addyi^® (flibanserin) - drug interaction overview. Raleigh, NC; 2015 Sep 3.

12. American Psychiatric Association. DSM-IV-TR: Diagnostic and statistical manual of mental disorders. 4th ed. Text revision. Washington, DC: American Psychiatric Association; 2000.

13. American Psychiatric Association. DSM-5: Diagnostic and statistical manual of mental disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013:433-7.

14. Simon JA, Kingsberg SA, Shumel B et al. Efficacy and safety of flibanserin in postmenopausal women with hypoactive sexual desire disorder: results of the SNOWDROP trial. Menopause . 2014; 21:633-40. [PubMed 24281236]

15. Jayne C, Simon JA, Taylor LV et al. Open-label extension study of flibanserin in women with hypoactive sexual desire disorder. J Sex Med . 2012; 9:3180-8. [PubMed 23057791]

16. Pfaus JG. Pathways of sexual desire. J Sex Med . 2009; 6:1506-33. [PubMed 19453889]

17. Stahl SM. Circuits of sexual desire in hypoactive sexual desire disorder. J Clin Psychiatry . 2010; 71:518-9. [PubMed 20492849]

18. Anon. Flibanserin (Addyi) for hypoactive sexual desire disorder. Med Lett Drugs Ther . 2015; 57:133-5. [PubMed 26375434]

19. Joffe HV, Chang C, Sewell C et al. FDA approval of flibanserin--treating hypoactive sexual desire disorder. N Engl J Med . 2016; 374:101-4. [PubMed 26649985]

20. US Food and Drug Administration. Drug development and drug interactions: table of substrates, inhibitors and inducers. From FDA website. Accessed 2016 Mar 1. [Web]

21. Robinson K, Cutler JB, Carris NW. First pharmacological therapy for hypoactive sexual desire disorder in premenopausal women: flibanserin. Ann Pharmacotherapy . 2016; 50:125-32.

22. Leiblum SR, Koochaki PE, Rodenberg CA et al. Hypoactive sexual desire disorder in postmenopausal women: US results from the Women's International Study of Health and Sexuality (WISHeS). Menopause . 2006; 13:46-56. [PubMed 16607098]

23. Stevens DM, Weems JM, Brown L et al. The pharmacodynamic effects of combined administration of flibanserin and alcohol. J Clin Pharm Ther . 2017; 42:598-606. [PubMed 28608926]

24. Beitz J. Letter from US Food and Drug Administration to Sprout Pharmaceuticals, Inc: Labeling order. Silver Spring, MD; 2019. From FDA website. [Web]

25. US Food and Drug Administration. FDA news release: FDA orders important safety labeling changes for Addyi. Silver Spring, MD; 2019 Apr 11. From FDA website. [Web]

26. Goldstein I, Kim NN, Clayton AH et al. Hypoactive Sexual Desire Disorder: International Society for the Study of Women's Sexual Health (ISSWSH) Expert Consensus Panel Review. Mayo Clin Proc . 2017; 92:114-128. [PubMed 27916394]

27. Clayton AH, Kingsberg SA, Goldstein I. Evaluation and Management of Hypoactive Sexual Desire Disorder. Sex Med . 2018; 6:59-74. [PubMed 29523488]

28. Clayton AH, Goldstein I, Kim NN et al. The International Society for the Study of Women's Sexual Health Process of Care for Management of Hypoactive Sexual Desire Disorder in Women. Mayo Clin Proc . 2018; 93:467-487. [PubMed 29545008]

29. US Food and Drug Administration. Center for Drug Evaluation and Research: Application number 0210557Orig1s000: Multi-discipline review. From FDA website. [Web]

30. Anon. Bremelanotide (Vyleesi) for Hypoactive Sexual Desire Disorder. Med Lett Drugs Ther . 2019; 61:114-116. [PubMed 31381550]